Scientists have found an antibody that inactivates all influenza A subtypes. The antibody binding site, tucked away in a stable region of the virus, might form the first lasting vaccine against flu.

The influenza virus constantly mutates, forcing scientists to play catch-up and produce a new seasonal vaccine each year. But Antonio Lanzavecchia, an immunologist at the Institute for Research in Biomedicine in Bellinzona, Switzerland, and an author on the new study, says that observing the human immune response to influenza convinced him that it would be possible to design a vaccine that prevails over mutation.

"During the 2009 H1N1 pandemic, we found some people with antibodies to multiple viral subtypes," says Lanzavecchia. Antibodies, which are produced by white blood cells called B cells, bind to specific target sites, inactivating viruses or flagging them for destruction by other immune cells.

Immune reaction

To test the cross-reactivity of influenza antibodies, the team screened B cells from eight human donors who had been infected with or immunized against different influenza strains. They took the B cells early in the immune response, when the repertoire of antibodies they secrete is at its most diverse.

After looking at 104,000 B cells, they hit the jackpot. "Our FI6 antibody is the first one ever found that reacts to all 16 of the influenza A subtypes," says Lanzavecchia.

The finding, published today in Science1, follows other reports of broadly reactive influenza antibodies, but these could only bind to either group 1 viruses, such as the H1N1 'swine flu' and the avian influenza H5N12, or group 2 viruses3, which include the seasonal H3N2 strains.

"Finding antibodies to all strains of one group was exciting," says immunologist Patrick Wilson from the University of Chicago, Illinois, who was not involved with the study, "but getting one to both groups is stunning."

The antibody itself is not a vaccine, but it could be an instruction manual for making one. The scientists say that a small protein mimicking the part of the virus bound by the FI6 antibody might cajole the immune system into making similarly cross-reactive antibodies.

Stem the attack

To zero in on the binding site, Lanzavecchia's team used X-ray crystallography. Their structure shows that the FI6 antibody binds to the stem region of influenza's haemagglutinin protein. Most influenza antibodies bind to more accessible head region of haemagglutinin.

Because much of the head region is not essential for viral function, it can mutate — allowing the virus to evade immune attack. By contrast, the stem region has a structure that is easily disrupted by mutations, so needs to stay stable.

"The stem is so well conserved between influenza subtypes that I would expect there to be high selective pressure against mutation in this area," says Wilson. He says there is a real chance a vaccine based on the haemagglutinin stem could work in humans. Previous work has shown that mice immunized with a small stem protein were protected against multiple influenza strains4.

Although Lanzavecchia admits that developing the FI6 binding site into a new vaccine may take years, he hopes that the antibody itself might be used as a treatment in the meantime. When the antibody binds to the virus, it stops it from infecting mammalian cells, and the researchers say that treating influenza with the antibody works in mice and ferrets.

"The animals survived infection with multiple different flu strains at doses that would usually kill them," says Lanzavecchia. "In humans, even reducing the viral load by 10% could help stop people getting sick."